Macrocytic Anaemia

Question 1

What are the 2 broad types of macrocytic anaemia?

Answer 1

Megaloblastic and non-megaloblastic depending on bone marrow findings

Question 2

What is the pathology underlying megaloblastic anaemia?

Answer 2

Megaloblastic anaemia is characterised by:

=> presence of erythroblasts with delayed nuclear maturation compared to the cytoplasm in the bone marrow

=> megaloblasts are large + have large immature nuclei

Question 3

What causes megaloblastic anaemia?

Answer 3

1. B12 deficiency ± abnormal metabolism
2. Folate deficiency ± abnormal metabolism
3. Other defects of DNA synthesis
4. Myelodysplasia

Question 4

What are the haematological changes in megaloblastic macrocytic anaemia?

Answer 4

High mean cell volume

If there is a coexisting cause of microcytic anaemia => dimorphic picture with either a low/normal MCV

Question 5

How is vitamin B12 absorbed?

Answer 5

Vitamin B12 is found in meat, eggs, fish and milk, not in plants.

Vitamin B12 binds to intrinsic factor (glycoprotein released by gastric parietal cells along with H+ ions) in the lumen.

Intrinsic factor delivers B12 to the receptors on the mucosa and B12 is taken up by enterocytes whilst intrinsic factor remains in the lumen.

Question 6

How is vitamin B12 transported?

Answer 6

Vitamin B12 is transported from enterocytes to the bone marrow bound to glycoprotein transcobalamin II.

In plasma, ~90% vitamin B12 is bound to transcobalamin I.

Question 7

What causes vitamin B12 deficiency?

Answer 7

Low dietary intake i.e. veganism

Impaired absorption:
i. Stomach
=> Pernicious anaemia
=> Gastrectomy
=> Congenital deficiency of intrinsic factor 

ii. Small bowel disease:
=> Ileal disease / resection
=> Bacterial overgrowth
=> Tropical sprue
=> Fish tapeworm 

Abnormal utilisation:
=> Congenital transcobalamin II deficiency
=> Nitrous oxide (inactivates B12)

Malabsorption:
=> Coeliac’s disease
=> Pancreatitis
=> Pernicious anaemia

Question 8

What is vitamin B12 also known as?

Answer 8

Cobalamin

Question 9

What is pernicious anaemia?

Answer 9

Pernicious anaemia:

=> autoimmune disease

=> atrophic gastritis with loss of parietal cells in the gastric mucosa => reduced/no intrinsic factor => B12 malabsorption

=> Parietal cell antibodies are found in 90% of people with pernicious anaemia

=> Intrinsic factor antibodies found in 50% of people with pernicious anaemia

Question 10

Who does pernicious anaemia affect?

Answer 10

Common in elderly

Women > men

Assoc. with other autoimmune diseases i.e. thyroid disease, Addison’s disease, vitiligo

*~50% of patients with pernicious anaemia have thyroid antibodies

Question 11

What are the clinical features of pernicious anaemia?

Answer 11

Insidious onset

Progressively increasing symptoms of anaemia

Lemon yellow colour due to pallor and milk jaundice - excess breakdown of haemoglobin

Glossitis / angular stomatitis

If untreated for a long time => irreversible neurological changes (only with very low levels of vitamin B12)

Neurological symptoms:
=> Polyneuropathy - progressively involving peripheral nerves, posterior and lateral columns of spinal cord (subacute combined denegeration)

=> Symmetrical paraesthesiae in fingers & toes

=> Early loss of vibration sense + proprioception

=> Progressive weakness

=> Ataxia

=> Paraplegia

=> Dementia ; psychiatric problem ; hallucinations ; delusions ; optic problems due to very low vitamin B12

Question 12

What are the differential diagnosis for pernicious anaemia?

Answer 12

Folate deficiency

Question 13

Where do you get folate intake from?

Answer 13

Folate is synthesised by gut bacteria.

Dietary intake: green vegetables i.e. spinach, broccoli ; liver, kidney ; nuts ; yeast

Folate is present in food as polyglutamates

Polyglutamates is reduced to dihydrofolate or tetrahydrofolate forms

Body stores last 4 months.

Folate is absorbed in duodenum / proximal jejunum.

Question 14

Causes of folate deficiency

I. Poor intake
=> Old age
=> Poor social conditions
=> Starvation
=> Alcohol excess (also causes impaired utilisation)

II. Poor intake due to anorexia
=> GI disease e.g. gastrectomy, coeliac’s disease, Crohn’s
=> Cancer

III. Anti-folate drugs
=> Anticonvulsants i.e. phenytoin
=> Methotrexate
=> Trimethoprim

Answer 14

IV. Excess utilisation

a) Physiology:
=> Pregnancy
=> Lactation
=> Prematurity

b) Pathology
=> Haematological disease with excess RBC e.g. haemolysis
=> Malignant disease with increased cell turnover
=> Inflammatory disease
=> Metabolic disease e.g. homocystinuria
=> Haemodialysis

V. Malabsorption
=> Small bowel disease

Question 15

When is folic acid supplements extremely important to give and why?

Answer 15

At the time of conception and in the first 12 weeks of pregnancy => reduces the incidence of neural tube defects

Question 16

What is the role of folate and vitamin B12?

Answer 16

DNA synthesis

Question 17

What does the blood film look like for megaloblastic anaemia?

Answer 17

Hypersegmented neutrophils

Oval macrocytes

Question 18

How do you investigate macrocytic anaemia?

Answer 18

1. Blood film: hypersegmented neutrophils in B12/folate deficiency
2. Bloods: LFT, TFT, serum B12, serum folate (only reflects recent intake), red cell folate (better indicator long term)
3. Bone marrow biopsy - indicated if the cause is not revealed by the above tests.

Bone marrow biopsy likely to show:

=> Megaloblastic marrow

=> Normoblastic marrow i.e. liver disease, hypothyroidism

=> Abnormal erythroiesis i.e. sideroblastic anaemia, leukaemia

=> Increased erythropoiesis i.e. haemolysis

Question 19

What is the management for megaloblastic macrocytic anaemia?

Answer 19

Hydroxocobalamin IM

Folic acid 5mg for 4 months + vitamin B12 always (risk of subacute combined generation of the cord if vitamin B12 too low)

*B12 is always given before folic acid
=> folic acid supplements without B12 might mask B12 deficiency, which can result in subacute combined generation of the cord.

Question 20

What is non-megaloblastic macrocytic anaemia?

Answer 20

Raised MCV + macrocytosis on peripheral blood film with normoblastic bone marrow

Normal levels of vitamin B12 and folate

Question 21

What causes non-megaloblastic anaemia?

Answer 21

Physiology i.e. Pregnancy

Pathology:

=> Alcohol

=> Liver disease

=> Reticulocytosis (due to haemolysis)

=> Hypothyroidism

=> Haematological disorders i.e. aplastic anaemia, myelodysplasia, multiple myeloma

=> Drugs i.e. hydroxycarbamide, azathioprine